Anticoagulation for Atrial Fibrillation: Who, When, and How? August 17, 2013 Elaine M. Hylek, MD, MPH Boston University School of Medicine

Disclosures Disclosures of Elaine Hylek Employment No conflict of interest to disclose Research support NIH/NINDS, NIH/NHLBI; Bristol-Myers Squibb-Executive Steering Committee; ARISTOTLE trial; Janssen-Executive Steering Committee; ORBIT-AF Registry Scientific advisory board Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer Consultancy Speakers bureau Major stockholder Patents Honoraria Bayer, Boehringer-Ingelheim, Pfizer Travel support Other

TEE depicting a large LAA thrombus attached to the lateral wall Hesse, B. et al. Circulation 2006;113:e456-457e

Stanford Stroke Center, Albers G

Stanford Stroke Center, Albers G

Prevalence of AF by Age Feinberg WM. Arch Intern Med. 1995;155(5):469–473 6

Budnitz D et al. N Engl J Med 2011;365:2002–12 HAZARDS OF WARFARIN Budnitz D et al. N Engl J Med 2011;365:2002–12

Budnitz D et al. N Engl J Med 2011;365:2002–12 HAZARDS OF WARFARIN Budnitz D et al. N Engl J Med 2011;365:2002–12

Efficacy and Safety Data for Target-Specific Oral Anticoagulants

RE-LY: Time to First Stroke/SEE RR 0.91 (95% CI: 0.74–1.11) p<0.001 (noninferiority) p=0.34 (superiority) 0.05 0.04 RRR 34% 1.69% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.03 Cumulative hazard rates 1.53% 0.02 RR 0.66 (95% CI: 0.53–0.82) p<0.001 (superiority) 1.11% 0.01 0.0 0.5 1.0 1.5 2.0 2.5 Years Connolly SJ et al. N Engl J Med 2009; 361:1139–51

RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism Connolly SJ., et al. NEJM Aug 30th 2009. DOI 10.1056/NEJMoa0905561

Hemorrhagic stroke 50 45 40 30 20 14 10 12 D110 mg BID D150 mg BID RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 0.38% RRR 69% RRR 74% 30 20 Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%. 14 10 12 0.12% 0.10% D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

Dabigatran Etexilate vs Warfarin (RE-LY) October 19, 2010 FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial Fibrillation PRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.

ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism   Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 Patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification Populations Patel et al. NEJM 2011;365:883-91

Key Secondary Efficacy Outcomes Rivaroxaban Warfarin Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034 Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.34 0.06 0.44 1.42 0.10 0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) 0.024 0.581 0.366 Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003 Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121 All Cause Mortality Vascular Non-vascular Unknown Cause 1.87 1.53 0.19 0.15 2.21 1.71 0.30 0.20 0.85 (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) 0.073 0.289 0.094 0.370 Patel et al. NEJM 2011;365:883-91

Safety Outcomes Rivaroxaban Warfarin Event Rate or N (Rate) HR (95% CI) P-value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) 0.576 0.019 0.044 0.007 0.003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.001 21% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011 No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 Granger C et al. NEJM 2011;365:981–92

Efficacy Outcomes Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI) P Value Event Rate (%/yr) Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 * Part of sequential testing sequence preserving the overall type I error Granger C et al. NEJM 2011;365:981–92

Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI) P Value Event Rate (%/yr) Primary safety outcome: ISTH major bleeding* 2.13 3.09 0.69 (0.60, 0.80) <0.001 Intracranial 0.33 0.80 0.42 (0.30, 0.58) Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding 4.07 6.01 0.68 (0.61, 0.75) GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) Any bleeding 18.1 25.8 0.71 (0.68, 0.75) * Part of sequential testing sequence preserving the overall type I error

You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271 ACCP Recommendations for Stroke Prevention Therapy CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B) CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy (Grade 1B) CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A) For recommendations in favor of oral AC, we suggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B) You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271

ESC 2012 UPDATE GUIDELINES For ATRIAL FIBRILLATION Camm J et al. Eur Heart J 2012;33:2719–47

2011 ACCF/AHA/HRS Focused Update Dabigatran is useful as an alternative to warfarin for the prevention of stroke in patients with AF. Selection of patients with AF and ≥1 risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran. Wann LS et al. Heart Rhythm 2011;8:e1–e8

Hylek, EM. J Cardiovasc Med 2009;10:605-09

Effect of TTR on Primary Endpoints In RELY 0.54 0.59 0.91 1.21 Wallentin, et al. Lancet 2010 24 24

10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI 5.65-6.59%), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI 0.85-1.00).

Translating the Results of Clinical Trials into Clinical Practice Patient selection Therapeutic implementation         Environment of the healthcare delivery system     Nallamothu, et al. Circulation 2008;118:1294–303

Will we be able to translate trial results to real-world practice? Revised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006.

New Oral Anticoagulants: Summary Property Dabigatran Rivaroxaban Apixaban Edoxaban Route of admin Oral Target Thrombin FXa Dosing Twice daily Once daily Monitoring required No Half-life (hrs) 12–17 9–12 8–15 8–11 Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%

Definitions: Chronic Kidney Disease and Renal Insufficiency Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation www.ckdsite.com I MILD I MOD I SEVERE I Renal Insufficiency Classification Slide courtesy of C Cove

Randomized Trial Age Baseline CrCl Exclusion CrCl ARISTOTLE ROCKET AF Apixaban 5 mg bid 70 83% ≥50 <25 ml/min Warfarin ROCKET AF Rivaroxaban 20 mg qd 73 67 (median) < 30 ml/min RE-LY Dabigatran 150 mg bid 72 68 (median) <30 ml/min 69 (median)

Pharmacokinetics with Varying Levels of Renal Dysfunction   Apixaban Dabigatran Rivaroxaban Elimination half life with CrCl >80 ml/min 7.6 hr 13.8 hr 8.3 hr CrCl 50–79 ml/min 7.3 hr 16.6 hr 8.7 hr CrCl 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr CrCl <30 ml/min 17.3 hr 27.5 hr 9.5 hr Am J Hematol. 2012 May;87 Suppl 1:S141-5. doi: 10.1002/ajh.23202. Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. skaatz1@hfhs.org. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. PMID: 22473649 Kaatz S et al. Am J Hematol 2012 Suppl 1:S141-5. PMID: 22473649

JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly. Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy. In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.

New Oral Anticoagulants: Summary Property Dabigatran Rivaroxaban Apixaban Edoxaban Route of admin Oral Target Thrombin FXa Dosing Twice daily Once daily Monitoring required No Half-life (hrs) 12–17 9–12 8–15 8–11 Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%

Polypharmacy and Non-adherence Strongest predictor of non-adherence is the # of medications Non-adherence rates estimated 25–50% Intentional about 75% of the time Changes in regimen made by patients to: increase convenience reduce adverse effects or decrease refill expense

Recommended Structured Follow-up First month and subsequent 3 month intervals

Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding Events UPDATED 11/02/2012. … bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

HAS-BLED Bleeding Risk Score Hypertension (SBP>160mmHg) Abnormal renal/liver fxn (1 pt for each) Stroke Bleeding history or prone Labile INR (if on warfarin) Elderly (>65 years) Drugs (ASA, NSAIDS)/alcohol (1 pt for each) Increasing score associated with ISTH major bleeding (C-index 0.72) Based on 3978 patients in the EuroHeart Survey on AF with complete follow-up, all univariate bleeding risk factors in this cohort were used in a multivariate analyses along with ‘historic’ bleeding risk factors. A new bleeding risk score (acronym HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly) was calculated, incorporating risk factors from the derivation cohort.Results: Fifty-three (1.5%) major bleeds occurred during 1-year follow-up. The annual bleeding rate rose with increasing risk factors. The predictive accuracy in the overall population using significant risk factors in the derivation cohort (c-statistic 0.72) was consistent when applied in several subgroups. Application of the new bleeding risk score (HAS-BLED) gave similar c-statistics except where patients were receiving antiplatelet agents alone or no antithrombotic therapy, with c-statistics of 0.91 and 0.85, respectively. Pisters R et al. Chest 2010;138:1093–100

Optimizing Benefit and Reducing Risk Hemorrhage Thrombosis AF stroke associated with a 30-day mortality of 24%.

Swedish AF Cohort; Circulation 2011; 125: 2298-2307

Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21 Dabigatran visits,% 2010Q4 2011 Q1 Q2 Q3 Q4 Atrial fibrillation 92 72 75 71 63 Venous thromboembolism 4 8 3 5 Hypertensive heart disease 13 15 14 Coronary artery disease 9 6 CVA/TIA Valvular disorders Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21

Effective Use of TSOACs in Clinical Practice 1. Patient selection – ADHERENCE Dose selection – creatinine clearance Determine interval follow-up Assess stability of renal function Blood pressure control Avoidance of concomitant antiplatelet therapy Package insert – avoid potent drug interactions, guidance on transitions

Procedural Management based on Bleeding Risk of Surgery DABIGATRAN APIXABAN/ RIVAROXABAN

Novel Anticoagulants Dabigatran 150 mg BID reduced ischemic stroke Dabigatran 80% renal clearance Dabigatran is associated with small risk of MI, but reduced cardiovascular mortality Dabigatran and rivaroxaban increase GI bleeding Rivaroxaban is once per day and approved Rx for VTE 6. Apixaban reduced stroke, major hemorrhage, and mortality 7. Well-controlled warfarin is associated with low rate of adverse events

Gaps: Practical Considerations Translation across indication Atrial fibrillation and valvular heart disease Atrial fibrillation and ACS Atrial fibrillation and DVT or PE Select situations in which monitoring would be desirable Reversibility-trauma, urgent surgery, life-threatening hemorrhage

Guide to the Management of Bleeding in Patients Taking NOAC Patients with bleeding on NOAC therapy Mild bleeding Moderate-Severe bleeding Life-threatening bleeding Delay next dose or discontinue treatment as appropriate Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal Hemodialysis ? Prothrombin Complex Concentrate? (Circulation 2011;124:1573-9) Consideration of rFVIIa or PCC Charcoal filtration ? Prothrombin Complex Concentrate (Circulation 2011;124:1573-9) Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

WILL THERE BE A CONTINUING ROLE FOR WARFARIN? 1. Mechanical heart valves 2. Cost 3. Pregnancy 4. Severe renal impairment 5. Drug Interactions 6. Lack of acceptance of no monitoring Reversal? Nonadherence 9. Intolerant of novel anticoagulant drug 47

Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions. Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy. Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice. . 48 48